Alkenylamevoalkanoylphenotfflazine



United States Patent ALKENYLAMINOALKANOYLPHENOTHIAZINE DERIVATIVES John W. Cusic, Skokie, Ill., assignor to G. D. Searle & Co., Chicago, 11]., a corporation of Illinois No Drawing. Application January 9, 1952, Serial N0. 265,731

3 Claims. (Cl. 260-243) This invention relates to compounds of the phenothiazine series having in the l0-position an aminoalkanoyl radical, to salts thereof, and to processes for producing such compounds. More particularly, this invention relates to new compositions of matter having the following general structural formula The compounds of the above general formula are useful as intermediates in the prepartion of complex organic molecules such as pharmaceuticals. They are also of value as antioxidant, antiseptic, and surface-active agents, as well 'as medicinal agents such as diuretic, cardiovascular, and antispasmodic drugs. It is an object of this invention to provide novel compositions of matter which are of value for the foregoing uses. It is a further object to provide simple and efficient methods for manufacturing such substances.

In the foregoing general structural formula, Alk represents lower alkylene radicals containing between 1 and 10 carbon atoms, and preferably having 1 to 3 carbon atoms between the CO and NRR' groups. The radical Alk is a bivalent radical derived from a saturated aliphatic hydrocarbon radical, and includes such radicals as methylene, ethylene, propylene, the butylenes, and amylenes, and trimethylene, tetramethylene, and polymethylene radicals containing 1 to 10 carbon atoms. The radical R represents a lower alkenyl radical such as 2-propenyl, Z-butenyl, 3-butenyl, Z-pentenyl, 3-pentenyl, 4-pentenyl and hexenyl, or an alkyl substitution product thereof as methylpropenyl, ethylbutenyl and the like. The radical R can be of the same type as radical R. It can also be a lower alkyl radical such as methyl, ethyl, straight-chained and branch-chained propyl, butyl, amyl or hexyl or a cycloalkyl radical such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, and ethylcyclohexyl. It can also be a lower aralkyl radical such as benzyl and phenethyl or a lower hydroxyalkyl radical such as hydroxyethyl, hydroxypropyl and hydroxybutyl.

The phenothiazine nucleus of the foregoing compounds may be substituted in the benzenoid rings by halogen, alkyl or alkoxyl radicals.

The amino compounds which make up this invention are only slightly soluble in water, but are generally soluble in the common organic solvents. They readily form salts with acids, which saltstare generally water soluble. Among the acids which are suitable for forming such salts are hydrochloric, hydrobromic, sulfuric, phosphoric,

2,694,706 Patented Nov. 16, 1954 ICC tartaric, citric, sulfamic, acetic, malic, maleic, benzoic, and similar common organic and inorganic acids which provide anions which are non-toxic in usual dosages. The 8-halogenated xanthines such as S-chlorotheophylline, '8-bromotheophylline, and 8-chlorotheobromine are also satisfactory. Salts may also be formed by reacting the basic ketones with reactive esters of strong acids, to form quaternary ammonium salts. Such salts can be formed, for example, by reaction with esters such as methyl iodide, methyl chloride, ethyl bromide, propyl chloride, ethylene bromohydrin, propylene chlorohydrin, benzyl chloride, phenethyl bromide, dimethyl sulfate, methyl toluenesult'onate, ethyl benzenesulfonate, p-acetoxyethyl bromide, and related esters.

The compounds of this invention may be prepared by treating a compound having the following formula wherein Alk is a lower alkylene radical, and X represents halogen, with a primary or secondary aliphatic or aliphatic-type amine of the formula HNRR, preferably at elevated temperature, in the presence of an inert solvent. In practice, it is preferred to use 2 or 3 moles of the amine for each mole of haloalkenoyl phenothiazine, in order that excess amine may bind the halogen acid split out during the reaction. It is preferred to run the reaction at temperatures of the range of 50-150 centigrade for a period of several hours. At the completion of the reaction, the amine salt is removed and the solution of the aminoalkanoyl phenothiazine base in the organic solvent is isolated. The base may be obtained in a state of purity by conventional procedures such as evaporation of the solvent and distillation, or the base may be converted to the acid addition salt by treatment of the solution with an equivalent amount of acid.

My invention is disclosed in further detail by the following examples, which present specific embodiments of my invention, without, however, limiting it in spirit or in scope. The amounts of materials are given in parts by weight.

Example 1 112 parts of phenothiazine and 73 parts of fl-chloropropionyl chloride in 550 parts of benzene are refluxed for 20 hours. The hot solution is filtered and evaporated. The residue of 10 B-chloropropionylphenothiazine is recrystallized from alcohol, and melts at 13S-136 C.

150 parts of 10-fi-chloropropionylphenothiazine and parts of plperidene in 870 parts of dry toluene are refluxed for 6 hours. The cooled solution is extracted with dilute mineral acid, and the acid extract is made all aline and extracted with ether. The ether extract is dried and evaporated. The residue of IO-B-piperidinopropionylphenothiazine distils at 220-230 C. at 3 millimeters pressure. It is converted to the hydrochloride by treating a dry ether solution of the base with absolute alcoholic hydrogen chloride. The hydrochloride so formed is recrystallized from isopropanol and melts at 203-205 C. By a reaction analogous to the foregoing but employmg morpholme instead of piperidine, there is formed 10- ,B morpholinopropionylphenothiazine which is a viscous hlgh-boilmg oil. By an alternative method 300 parts of 1 0-,8-chloropropionylphenothiazine, 300 parts of morpholme, and 10 parts of potassium iodide in 800 parts of methyl ethyl ketone are heated at reflux temperature for 12 hours, cooled, and treated with dilute hydrochloric acid. The aqueous layer is separated and upon treatment with ether the crystalline hydrochloride of the IO-B-morpholinopropionylphenothiazine is obtained which, recrystallized from a mixture of isopropanol and ether, melts at about ZZZ-223 C.

Example 2 29 parts of 10 8-chloropropionylphenothiazine and 12 parts of diniethylamine in 80 parts of methyl ethyl ketone containing 0.5-" part ofpotassium iodideare "heated ina closed vessel at 6 65 C; for 48 hours. The cooled reaction mixture is extracted with dilute mineral acid.

. The mineralacid:s0lution-:is 'made-alkaline and extracted with ether. L :After:.removal bfzthe ethen the -residue 0f 10 dimethylaminopropionylphenothiazine' is crystallized-:fronuipetroleum. ether and-"melts at 86-88 C.

.When .dissolveddneether land .treated with absolute -.alcoholichydrogen ichloridegv it forms a crystalline: hydrochloride.

In a similanmanner:using-Bfi partsof dibutylamine in .placetofizthez climethylamine .one obtains lOqS-dibutylaminopropionylphenothiazine, awhich has the following strueturaltformula Example 3 iExample-4 parts QfJPhEQQthiaZiHe. and 36 parts of fi-chlorobutyryl ;hl0j1 6, tin .350; parts; ofndrys toluene are: refluxed f r. about 2153110 118. iiThclhobasolution is treated with d lqrizingi: hfir nal, sfiltered and -.evaporated. The resi e. :O 10131111orobutyrylphenothiazine is recrystallized from-aleQhohandnmel-ts at 158+L60a C.

51 :pnrts of;r1orfirchlorobutyrylphenothiazine.and @1 8 parts of dimethylaminednBOipartsioft acetone containing 1 part of potassium iodide are heated in a closedyesseliat 60 C. for 5 days. Atitheendbf that time the solution is evaporated and the residuc oflQ-fl dimethylaminobutyrylphenothiazine crystallizes "on standing. After recrystallization from'petroleum etherfthe basemelts at 90-9l C. "The hydrochloride is 'prepared bytrea'ting a'dry etherbenzene; solution of the base with absolute. alcoholic hydrogen chloride. The 3 dimethylaminobutyrylphenothiazine'hydrochloride is recrystajllizedifrom methyl ethyl ketone in the presence'offdecolorizing charcoal, and melts at 136'l38 C.

By the reaction of the same quantities of lO-y-chlorobutyrylphenothiazine "(producedfrom phenothiazine and 'y-chlorobutyryl chloride f by the above process) and dimethylamine in acetone containing a trace of potassium iodide there is formedl0--y dimethylaminobutyrylphenothiazine, which, recrystallized from petroleum ether, melts at about '9394"C. The hydrochloride melts at about l90192 C.

Example 5 parts of 10-;3-dimethylaminobutyrylphenothiazmg and 8 parts of methyl chloride in 60 parts of methyl ethyl ketone .are heated .in a closed vessel for A2 hour at 60 C.-and allowed to stand for 15 hours at room tempernture. The heavy precipitate of the quaternary salt, 10-B-dimethylaminobutyrylphenothiazine methochloride, is removed by filtration, dried and recrystallized from isopropanol. 'llhissalt .melts at 21.0-2l2 C.

By the same'procedure, using 20.-parts;of benzyl chloride, there is-formed the.-corresponding= quaternary salt, 1 O-fi-dimethylaminobutyrylphenothiazine benzylchloride.

Example 7 6 Other compounds which are produced by the foregoing procedures includethe following:

A. 10-fl-isopropylaminovalerylphenothiazine B. 10- -pyrrolidinobutyfylphenothiazine N''c0+cHi0Hicm.N

C. 1O-methylethylaminoacetylphenothiazine CHzCHt D. l0- 3-dimethy,laminopropionylphenothiazine 5 -monoxide N-oxide o 0 N-C o-cnrom-mcmn 10 -',B dibutylaminopropionylphenothiazine .5 -monoxide.

. .mixture. of. 5 8 parts of -1 0-18-chloropropionylphenoth1az1neand 40; parts of: idiethylamine 1'n2J12O2; parts :of methyl ethyl .ketone-containing l part of potassiumiiodide 1s.-heated ;in.a closed =reactor.for:5 days-.atr-i65 11C. 'l At .theend -of.-this period: the solyentiisrernoved and a: portron of the residue of 10-fi-diethylaminopropionylpheno- .thiazine 1s=distilled at'2l-0.2l2 ,Cnat 21n1m.-.pressure.* It crtn2sca crystalline. hydrochloride meltinguateabout "163-- '.By the, same method; 101 parts;of I-Oefl-chloropropionylphenothlazme are reactediwith 7;:parts ofi m'ethylethanolamine .andnthere. is EPI'ddUCCd'. 1'0-.- 3=methylethanolaniinoproplonylphenothiazine;rwhiclrhas the formula E-xample 7 Recrystallized'from ethanol it me1ts at about 129-1-30"C.

.Example. 8

' parts vof 1(lafirdiethylaminopropionylphenbthiazine, prepared as 1n"Example"7, are .treated with122'8; partsof methyl 1od1dein"400 parts of methylethyl ketone at 0C. for 1 hourandthen treated with ether. An-.dily;,preeipitate' forms which solidifies .on standing for sever al2hours. Recrystallizedfrom ethanol, the tmethiodide-nf LO-firdieth3y lanmopropionylphenothiazine- .melts at about 202- 'Upon :additiomof 15.0 parts .ofvmethyl bromide to a solu t1on of .parts of '10 3 diethylamingpropionylphenothiazine in .400;pa1".ts.of methyl ethyl'rketone, an oily precipitate ,forms: whichv solidifies. on.;stand-ing. -;The.crystallineine'thobroniidemelts at about 202- -204 C. i

Example 9 1 A mixture of 289 parts of l-,8-chloropropionylphenothiazine and 250 parts of n-hexylamine in 1600 parts of toluene is heated at reflux temperature for 3 hours and then treated with dilute hydrochloric acid. The resulting precipitate is collected on a filter and recrystallized from ethanol. The hydrochloride of IO-fi-n-hexylaminopropionylphenothiazine melts at about 191-192 C.

Example 10 289 parts of lO-fi-chloropropionylphenothiazine are heated at reflux temperature for 2 days with 297 parts of cyclohexylamine and 10 parts of potassium iodide in 800 parts of methyl ethyl ketone and then concentrated and treated with ice and hydrochloric acid. The aqueous layer is separated and treated with benzene. On standing the 10-,8-cyclohexylaminopropionylphenothiazine precipitates. Recrystallized from dilute isopropanol it melts at about 206-207 C. with decomposition.

Example 11 N-C 0-0 H2CHsI:IH-CHr-CH=CH I not Example 12 A mixture of 289 parts of 10- 3-chloropropionylphenothiazine, 194 parts of diallylamine and 10 parts of potassium iodide in 800 parts of methyl ethyl ketone is heated at reflux temperature for 3 days and then concentrated and treated with ice, hydrochloric acid, and ether. The aqueous layer is separated, rendered alkaline by addition of dilute sodium hydroxide, and extracted with ether. This ether extract is dried and evaporated to yield 10-18- diallylaminopropionylphenothiazine as an oil. Treatment of an ether solution of this oil with an equivalent of alcoholic hydrogen chloride and recrystallization of the precipitate yields a crystalline hydrochloride melting at about 131-133 C. It has the structural formula not Example 13 100 parts of phenothiazine and 86 parts of w-chlorocaproyl chloride in 800 parts of anhydrous toluene are heated at reflux temperature for 15 hours. The hot solution is stirred with decolorizing charcoal, filtered and evaporated to yield l0-w-chlorocaproylphenothlazme.

33 parts of this chloride and 12 parts of N-ethyl-amethyl-fi-butenylamine, distilled at l45150 C., in 80 parts of toluene are heated at reflux temperature for 3 days and then treated with dilute hydrochloric acid. The aqueous layer is separated, washed with ether, rendered alkaline by addition of potassium hydroxide, and extracted with ether. This extract is dried, stirred with decolorizing charcoal, filtered and evaporated to yield an amber, viscous oil. The -w-[N-ethyl-N-(a-methyl-flbutenyl)aminolcaproylphenothiazine has the structural formula Reaction of parts of l0- 8-chloropropionylphenothiazine and 65 parts of N-methylallylamine in 200 parts of toluene by the same procedure yields the IO-fl-(N- methyl-N-allylamino)propionylphenothiazine of the structural formula Example 14 A mixture of 300 parts of 10-B-chlorobutyrylphenothiazine and parts of N-benzylcrotylamine in 2000 parts of toluene is heated at reflux temperature for 5 days and then treated with dilute hydrochloric acid. The aqueous layer is separated, Washed With ether, rendered alkaline by addition ot sodium hydroxide, and extracted with ether. This extract is dried, stirred with decolorizing charcoal, filtered and evaporated to yield the IO-fl-(N-benzyDcrotylaminobutyrylphenothiazine as a light yellow, viscous, high boiling oil. Treatment of a solution of 30 parts of this base in 200 parts of methyl ethyl ketone with 10 parts of ethyl bromide at 80 C. for 3 hours yields the ethobromide, which has the structural formula propylaminoacetylphenothiazine as a yellowish, viscous, high boiling oil of the structural formula I claim: 1. An aminoalkanoylphenothiazine having the formula wherein Alk is a lower alkylene radical, and R is a member of the class consisting of hydrogen, and allyl radicals.

2. A compound of the structural formula 

1. AN AMINOALKANOYLPHENOTHIAZINE HAVING THE FORMULA 